Head and neck squamous cell carcinoma (HNSCC) frequently develops resistance to immune checkpoint blockade (ICB) therapy, resulting from an immune-excluded microenvironment. Immunogenic cell death (ICD) can increase tumor immunogenicity and further augment immune-cell infiltration by releasing immunogenic molecules. Hence, inducing ICD within tumors might be a promising strategy to restore antitumor immunity and sensitize HNSCC to ICB. Herein, we developed shikonin (SHK)-loaded, CGKRK-modified lipid nanoparticles (C-SNPs) and demonstrated that C-SNPs could enrich in tumor cells and induce necroptosis in vitro and in vivo. Transcriptomic profiling revealed that C-SNPs suppressed tumor-cell mismatch repair, which later activated the cGAS-mediated IFN response and further increased the expression of PD-L1. Combining C-SNPs with an anti-PD-1 antibody increased the infiltration of DCs and CD8+ T cells, yet the response was limited. Modifying C-SNPs with Mn2+ (C-SMNPs) enhanced the activation of cGAS-STING signaling and further boosted the maturation of DCs and the differentiation of cytotoxic T cells within ICB-treated tumors. Importantly, compared to C-SNPs, the combination of C-SMNPs with ICB resulted in more sustained tumor suppression in vivo. Together, we developed a versatile nanoparticle that delivered SHK and Mn2+ which sensitized HNSCC to ICB by disrupting tumor-cell mismatch repair and boosting the cGAS-STING-mediated IFN response. This nanosized ICD inducer-based strategy holds therapeutic potential in synergizing with anti-PD-1 immunotherapy to enhance treatment efficacy in HNSCC.